Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Jensen rat sarcoma cells in culture require L-asparagine for growth and lack detectable levels of asparagine synthetase. Cultures exposed for 24 h to graded concentrations of 5-azacytidine give rise to asparagine-independent variants in high frequency. These prototrophs are stable phenotypically whether maintained in the presence or absence of L-asparagine. Asparagine synthetase activity in several variant clones was uniform in thermolability and several kinetic parameters, as well as in immunological properties. Parental Jensen rat sarcoma cells contained no detectable immunologically cross-reacting material. Our data suggest that transitions between asparagine dependence and independence in these cells are mediated by stable shifts in gene expression rather than by structural gene mutations.
Mol Cell Biol 1983 Nov
PMID:Properties of asparagine synthetase in asparagine-independent variants of Jensen rat sarcoma cells induced by 5-azacytidine. 619 24

We have previously shown that asparagine synthetase (AS) mRNA expression can be dramatically up-regulated by asparagine deprivation in ts11 cells, mutants of BHK hamster cells which encode a temperature-sensitive AS. The expression of AS mRNA was also induced upon starvation for one of several essential amino acids in HeLa cells. We also showed that regulation of AS mRNA expression by amino acid concentration has both transcriptional and posttranscriptional components. Here we report the analysis of the elements in the human AS promoter region important for its basal activity and activation by amino acid starvation. Our results indicate that a DNA fragment spanning from nucleotides -164 to +44 of the AS promoter is sufficient for uninduced and induced gene expression. Mutations in a region located 15 to 30 bp downstream from the major transcription start site that shows good homology to a sequence in the first exon of c-fos implicated as a negative regulatory element resulted in a significant increase in basal gene expression but did not affect regulation. Interestingly, this region binds single-stranded-DNA-binding proteins that are specific for the AS coding strand. Mutations in either one of two putative binding sites for transcription factor Sp1, in a region of approximately 60 bp where many minor RNA start sites are located, or at the major transcription start site decreased promoter activity, but significant induction by amino acid starvation was still observed. Strikingly, mutations centered around nucleotide -68 not only decreased the basal promoter activity but also abolished amino acid regulation. This DNA region contains the sequence 5'-CATGATG-3', which we call the amino acid response element (AARE), that can bind a factor(s) present in HeLa cells nuclear extracts that is not capable of binding to an AS promoter with mutations or deletions of the AARE. This finding is in line with the hypothesis that transcriptional activation of AS gene expression is mediated through the binding of a positive regulatory element. We did not detect changes in the level of binding of this factor to the AARE by using nuclear extracts from HeLa cells grown under starved conditions, suggesting that activation of this factor(s) results from posttranslational modification or complexing with other proteins that do not affect its DNA-binding properties.
Mol Cell Biol 1993 Jun
PMID:Cis- and trans-acting elements involved in amino acid regulation of asparagine synthetase gene expression. 809 42

Gene amplification is commonly observed in primary tumors and established drug-resistant cell lines, both of which are generally aneuploid. However, this process is undetectable (frequency < 10(-9) in normal diploid mammalian cell lines. To investigate whether gene amplification can occur in pluripotent diploid cells, we have selected drug-resistant mutants of mouse embryonic stem (ES) cells. We had previously found that Chinese hamster ovary (CHO) and human cell lines selected in albizziin (Alb), an amino acid analog of L-glutamine, overexpress asparagine synthetase (AS) due to gene amplification. The same drug selection system was applied to ES cells to isolate single-step and multistep drug-resistant mutants. Albizziin-resistant ES cells exhibited elevated levels of AS; however, drug resistance in ES cells was associated with mRNA overexpression without gene amplification. AS gene amplification was observed in only one drug-resistant cell line and was preceded by AS mRNA overexpression. Gene amplification in the latter coincided with the loss of the pluripotent nature of the ES cells.
Somat Cell Mol Genet 1993 Jul
PMID:Overexpression of asparagine synthetase in albizziin-resistant murine diploid embryonic stem cells. 810 42

More than 600 potentially nodule-specific clones have been detected by differential hybridization of a broadbean cDNA library constructed from root nodule poly(A)+ RNA. These isolated cDNAs belong to at least 28 different clone groups containing cross-hybridizing sequences. The number of clones within a clone group varies from about 200 to only one single clone. Northern hybridization experiments revealed nodule-specific transcripts for 14 clone groups and markedly nodule-enhanced transcripts for another 7 clone groups. Sequence homologies indicate that three transcript sequences code for different leghemoglobins. Two other transcripts encode a nodule-specific sucrose synthase and a nodule-enhanced asparagine synthetase, respectively. Four deduced gene products are proline-rich, two of them being the homologues of PsENOD2 and PsENOD12. The third proline-rich protein (PRP) is composed of similar amino acid repeats as the nodule-specific PsENOD12 but is expressed in nodules and roots in comparable amounts. The fourth PRP is a nodule-enhanced extensin-type protein built up by Ser-Pro4 repeats. Two further nodule-specific transcripts encode gene products showing some similarity to structural glycine-rich proteins. Additionally, transcripts could be identified for broadbean homologues of the nodulins MsNOD25, PsENOD3 and PsENOD5 and transcripts specifying a nodule-enhanced lipoxygenase and a translation elongation factor EF-1 alpha, which is expressed in all broadbean tissues tested.
Plant Mol Biol 1993 Sep
PMID:A survey of transcripts expressed specifically in root nodules of broadbean (Vicia faba L.). 840 Jan 40

Genes encoding the ammonia-dependent asparagine synthetase (asnA) and asparaginyl-tRNA synthetase (asnS) have been cloned from Lactobacillus bulgaricus ATCC 11842. The nucleotide sequence suggests that asnA and asnS are organized as one operon and regulated by the tRNA-directed transcription antitermination mechanism (T. M. Henkin, Mol. Microbiol. 13:381-387, 1994).
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PMID:Lactobacillus bulgaricus asparagine synthetase and asparaginyl-tRNA synthetase: coregulation by transcription antitermination? 863 57

We have cloned and sequenced cDNA of asparagine synthetase (AS) from rat Sertoli cells. The nucleotide sequence was derived by analysis of cloned cDNA of reverse transcription-polymerase chain reaction (RT-PCR) product that spanned overall the cDNA coding region. The sequence contains three nucleotide differences when compared with that of rat Fao hepatoma cells (Hutson, R.G., and Kilberg, M.S. (1994) Biochem. J. 304, 745-750). Accordingly, amino acid residues Ser at position 330 and His at 491 of Sertoli cells were replaced by Pro and Tyr, respectively, in the sequence of the hepatoma cells. Mutational nucleotide changes may occur during carcinogenesis. The testis contained the most abundant AS mRNA among the tissues studied and others revealed by far a little amount of message. Expressions of AS mRNA in the liver and brain were high in fetal period and reduced rapidly after birth, showing importance of AS in cell proliferation.
Biochem Mol Biol Int 1996 Feb
PMID:Cloning of cDNA for asparagine synthetase from rat Sertoli cell. 893 34

Two new yeast genes, named ASN1 and ASN2, were isolated by complementation of the growth defect of an asparagine auxotrophic mutant. Genetical analysis indicates that these two genes are allelic to the asnA and asnB loci described previously. Simultaneous disruption of both genes leads to a total asparagine auxotrophy, while disruption of asn1 or asn2 alone has no effect on growth under tested conditions. Nucleotide sequences of ASN1 and ASN2 revealed striking similarities with genes encoding asparagine synthetase (AS) from other organisms. Regulation of ASN1 and ASN2 expression was studied using lacZ fusions and both genes were found to be several times less expressed in the absence of the transcription activator Gcn4p. The HAP complex, another transcription factor that binds to CCAAT-box sequences, was shown to specifically affect ASN1 expression. Hap2p and Hap3p subunits of the HAP complex are required for optimal expression of ASN1, while the Hap4p regulatory subunit, which is required for regulation by the carbon source, plays a minor role in this process. Consistent with the weak effect of Hap4p, the carbon source does not significantly affect expression of ASN1. Our results show that the role of the HAP complex is not limited to activation of genes required for respiratory metabolism.
Mol Microbiol 1996 Nov
PMID:Cloning of the ASN1 and ASN2 genes encoding asparagine synthetases in Saccharomyces cerevisiae: differential regulation by the CCAAT-box-binding factor. 895 15

Two cDNA clones (SAS1 and SAS2) encoding different isoforms of asparagine synthetase (AS; EC 6.3.5.4) were isolated. Their DNA sequences were determined and compared. The amino-terminal residues of the predicted SAS1 and SAS2 proteins were identical to those of the glutamine binding domain of AS from pea, asparagus, Arabidopsis and human, suggesting that SAS1 and SAS2 cDNAs encode the glutamine-dependent form of AS. The open reading frames of SAS1 and SAS2 encode a protein of 579 and 581 amino acids with predicted molecular weights of 65182 and 65608 Da respectively. Similarity of the deduced amino acid sequences of SAS1 and SAS2 with other known AS sequences were 92% and 93% for pea AS1; 91% and 96% for pea AS2; 88% and 91% for asparagus; 88% and 90.5% for Arabidopsis; 70.5% and 72.5% for E. coli asnB and 61% and 63% for man. A plasmid, pSAS2E, was constructed to express the soybean AS protein in Escherichia coli. Complementation experiments revealed that the soybean AS protein was functional in E. coli. Southern blot analysis indicated that the soybean AS is part of a small gene family. AS transcript was expressed in all tissues examined, but higher levels were seen in stem and root of light-grown tissue and leaves of dark-treated tissue.
Plant Mol Biol 1997 Jan
PMID:Molecular cloning and expression of two cDNAs encoding asparagine synthetase in soybean. 903 48

The enzymatic synthesis of asparagine is an ATP-dependent process that utilizes the nitrogen atom derived from either glutamine or ammonia. Despite a long history of kinetic and mechanistic investigation, there is no universally accepted catalytic mechanism for this seemingly straightforward carboxyl group activating enzyme, especially as regards those steps immediately preceding amide bond formation. This chapter considers four issues dealing with the mechanism: (a) the structural organization of the active site(s) partaking in glutamine utilization and aspartate activation; (b) the relationship of asparagine synthetase to other amidotransferases; (c) the way in which ATP is used to activate the beta-carboxyl group; and (d) the detailed mechanism by which nitrogen is transferred.
Adv Enzymol Relat Areas Mol Biol 1998
PMID:Mechanistic issues in asparagine synthetase catalysis. 955 53

The sequence and genomic organization of the human Golfalpha (GNAL) gene were determined. The human GNAL gene was found to contain 12 coding exons, and it spans over 80 kb on chromosome 18p11. 5' RACE analysis suggested an additional transcription initiation start site. Sequence analysis of the putative promoter region revealed conserved binding sites for several transcription factors. Sequence analysis of the 3'-untranslated region revealed the presence of two Alu sequences and two polyadenylation signals. 3' RACE analysis confirmed the functionality of the most downstream poly-a signal. The human GNAL was found to be expressed as a single transcript of about 5.9 kb in the brain. One highly informative dinucleotide repeat was found in intron 5. Additionally, a processed pseudogene for asparagine synthetase was found about 6 kb upstream of the GNAL gene. Knowledge of the sequence and structure of the human GNAL gene provides essential information for further analysis of the GNAL locus at chromosome 18p11 which has been linked to bipolar disorder and schizophrenia.
Mol Psychiatry 2000 Sep
PMID:Sequence and genomic organization of the human G-protein Golfalpha gene (GNAL) on chromosome 18p11, a susceptibility region for bipolar disorder and schizophrenia. 1103 82


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